Gigantol ameliorates DSS-induced colitis via suppressing ß2 integrin mediated adhesion and chemotaxis of macrophage.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium, recognized as "Shihu" in traditional Chinese medicine, holds a rich history of medicinal utilization documented in the Chinese Pharmacopoeia. Ancient texts like "Shen Nong Ben Cao Jing" extol Dendrobium's virtues as a superior herbal medicine fortifying "Yin" and invigorating the five viscera. Dendrobium is extensively employed for the treatment of gastrointestinal inflammatory disorders, showcasing significant therapeutic efficacy, particularly against ulcerative colitis (UC), within the realm of Chinese ethnopharmacology. Dendrobium plays crucial pharmacological roles due to its rich content of polysaccharides, alkaloids, phenanthrenes, and bibenzyls. Gigantol, a prominent bibenzyl compound, stands out as one of the most vital active constituents within Dendrobium, the gigantol content of Dendrobium leaves can reach approximately 4.79 µg/g. Its significance lies in being recognized as a noteworthy anti-inflammatory compound derived from Dendrobium. AIM OF THE STUDY: Given the pivotal role of gigantol as a primary active substance in Dendrobium, the therapeutic potential of gigantol for gastrointestinal diseases remains enigmatic. Our present investigation aimed to evaluate the therapeutic effects of gigantol on dextran sulfate sodium (DSS)-induced colitis and reveal its potential mechanism in countering UC activity. MATERIALS AND METHODS: The protective efficacy of gigantol against colitis was assessed by examining the histopathological changes and conducting biochemical analyses of colon from DSS-challenged mice. Assessments focused on gigantol's impact on improving the intestinal epithelial barrier and its anti-inflammatory effects in colonic tissues of colitis mice. Investigative techniques included the exploration of the macrophage inflammatory signaling pathway via qPCR and Western blot analyses. In vitro studies scrutinized macrophage adhesion, migration, and chemotaxis utilizing transwell and Zigmond chambers. Furthermore, F-actin and Rac1 activation assays detailed cellular cytoskeletal remodeling. The potential therapeutic target of gigantol was identified and validated through protein binding analysis, competitive enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assay. The binding sites between gigantol and its target were predicted via molecular docking. RESULTS: Gigantol ameliorated symptoms of DSS-induced colitis, rectified damage to the intestinal barrier, and suppressed the production of pro-inflammatory cytokines in colonic tissues. Intriguingly, gigantol significantly curtailed NF-κB signaling activation in the colons of DSS-induced colitis mice. Notably, gigantol impaired the ß2 integrin-dependent adhesion and migratory capacity of RAW264.7 cells. Moreover, gigantol notably influenced the cytoskeleton remodeling of RAW264.7 cells by suppressing Vav1 phosphorylation and Rac1 activation. Mechanistically, gigantol interacted with ß2 integrin, subsequently diminishing binding affinity with intercellular adhesion molecule-1 (ICAM-1). CONCLUSIONS: In conclusion, these findings elucidate that gigantol ameliorates DSS-induced colitis by antagonizing ß2 integrin-mediated macrophage adhesion, migration, and chemotaxis, thus it may impede macrophage recruitment and infiltration into colonic tissues. This study suggests that gigantol shows promise as a viable candidate for clinical colitis therapy.

Decoding the synergistic potential of MAZ-51 and zingerone as therapy for melanoma treatment in alignment with sustainable development goals.

Melanoma, an invasive class of skin cancer, originates from mutations in melanocytes, the pigment-producing cells. Globally, approximately 132,000 new cases are reported each year, and in South Africa, the incidence stands at 2.7 per 100,000 people, signifying a worrisome surge in melanoma rates. Therefore, there is a need to explore treatment modalities that will target melanoma's signalling pathways. Melanoma metastasis is aided by ligand activity of transforming growth factor-beta 1 (TGF-ß1), vascular endothelial growth factor-C (VEGF-C) and C-X-C chemokine ligand 12 (CXCL12) which bind to their receptors and promote tumour cell survival, lymphangiogenesis and chemotaxis. (3-(4-dimethylaminonaphthelen-1-ylmethylene)-1,3-dihydroindol-2-one) MAZ-51 is an indolinone-based molecule that inhibits VEGF-C induced phosphorylation of vascular endothelial growth factor receptor 3 (VEGFR-3). Despite the successful use of conventional cancer therapies, patients endure adverse side effects and cancer drug resistance. Moreover, conventional therapies are toxic to the environment and caregivers. The use of medicinal plants and their phytochemical constituents in cancer treatment strategies has become more widespread because of the rise in drug resistance and the development of unfavourable side effects. Zingerone, a phytochemical derived from ginger exhibits various pharmacological properties positioning it as a promising candidate for cancer treatment. This review provides an overview of melanoma biology and the intracellular signalling pathways promoting cell survival, proliferation and adhesion. There is a need to align health and environmental objectives within sustainable development goals 3 (good health and well-being), 13 (climate action) and 15 (life on land) to promote early detection of skin cancer, enhance sun-safe practices, mitigation of environmental factors and advancing the preservation of biodiversity, including medicinal plants. Thus, this review discusses the impact of cytostatic cancer drugs on patients and the environment and examines the potential use of phytochemicals as adjuvant therapy.

The anti-oxidative potential of ginger extract and its constituent on meat protein isolate under induced Fenton oxidation.

Ginger extract has been reported to possess antioxidant properties. However, components isolated from ginger have been rarely reported to inhibit oxidation. Herein, the antioxidant properties of ginger and purified components derived from it (6-gingerol, zingerone, rutin, quercetin, and kaempferol) were confirmed by using HPLC and were further used to investigate its effect on lamb meat. Myofibrillar proteins isolated (MPI) from lamb meat were incubated with ginger and its constituents under induced Fenton oxidation (1.0 mmol/L FeCl3, 0.1 mmol/L Asc, and 20 mmol/L H2O2) for 1, 3,5, and 7 h. Incubating meat protein isolate in the absence of ginger extract or its components resulted in a substantial drop in sulfhydryl groups, an increase in protein carbonyl content, and a corresponding increase in TBARS content. However, ginger extract and its constituents demonstrated antioxidant properties, which might be attributed to their hydroxyl groups and suitable solubilizing side chains. Overall, ginger extract exhibited the highest antioxidant capabilities of all treated samples, suggesting that ginger extracts may be used as a natural antioxidant in meat and lipid/protein-containing processed products. SIGNIFICANCE OF THE STUDY: Ginger extract is also frequently used as a herbal medicine due to its anti-inflammatory, anti-cancer, and antibacterial qualities. Nonvolatile pungent chemicals found in ginger, such as gingerol, shogaols, paradols, and zingerone, as well as kaempferol, rutin, and other phenolic compounds, have been confirmed in ginger extract and have been shown to have antioxidant action driven by free radical elimination. Despite these findings, ginger extract and its pure constituent components have seldom been shown to have the ability to slow protein and lipid oxidation in meat and meat-related products. The effect of ginger extracts on the oxidative stability of myofibriller protein isolate has never been investigated. Exploiting the phenolic content of ginger extract may result in a discovery that would have a huge influence on both the ginger and meat industries as well as other food processing sectors. The first aim of our study was to confirm the presence of six selected phenolic compounds (rutin, kaempferol, 6-gingerol, zingerone, naringenin, and quercetin) in ginger as reported by literature, and the second objective was to determine the efficacy of ginger extracts and its purified constituents on myofibrillar protein isolate treated under induced Fenton oxidation.

Protective Effects of Zingerone Against Depression-Like Behavior and Biochemical Changes in Chronic Stressed Rats: Antioxidant Effects.

Ginger contains zingerone, an active constituent possessing antioxidant and neuroprotective properties. The present study was designed to explore the efficacy of the bioactive compound, zingerone, for treating behavioral and biochemical alterations in rats exposed to chronic restraint stress (CRS). Female Wistar rats were administered zingerone (25, 50, and 100 mg/kg p.o.) once daily for a period of 28 days while being exposed to CRS (6 h/day). Our results indicated that the stressed animals depicted depression-like behavior (reduced sucrose preference and increased immobility time) associated with increased lipid peroxidation (LPO) (cortex), decreased catalase (CAT) (hippocampus and cortex), and increased superoxide dismutase (SOD) (hippocampus and cortex). In addition, metabolic alterations were characterized by hyperglycemia and increased glycosylated hemoglobin in the CRS rats. However, no alterations were observed for learning and memory and in the levels of reduced glutathione. Repeated zingerone administration significantly reversed depression-like behavior elicited by CRS in rats. Furthermore, a significant antioxidant effect was exhibited by zingerone, as shown by decreased LPO and enhanced activity of SOD and CAT in chronically stressed rats. The findings of our study demonstrated that zingerone possesses protective actions against chronic stress-induced depressive-like behavioral, biochemical, and metabolic alterations and that its underlying mechanism may be attributed to its antioxidant properties. The results also signify its pharmacological and possible nutritional importance.

Short-term treatment with zingerone ameliorates dextran sulfate sodium-induced mouse experimental colitis.

BACKGROUND: Ulcerative colitis (UC) is a relapsing and chronic inflammatory disease of the gastrointestinal tract, which seriously threatens human health. Zingerone (ZO) has been proven to be effective for many diseases. The purpose of this study is to investigate the protective effects and potential mechanisms of ZO extracted from ginger on dextran sulfate sodium (DSS)-induced mouse ulcerative colitis (UC). RESULTS: The results showed that ZO alleviated the weight loss of UC model mice, reduced the disease activity index scores, and inhibited the shortening of colon length. ZO also improved DSS-induced pathological changes in colon tissue and inhibited the secretion of pro-inflammatory cytokines in colon and mesenteric lymph nodes. Further mechanism analysis found that ZO inhibited DSS-induced nuclear factor-κB pathway activation, and regulated peroxisome proliferator-activated receptor γ (PPARγ) expression. To further explore whether PPARγ was involved in the anti-UC effect of ZO, PPARγ inhibitor GW9662 was used. Although ZO also showed a protective effect on GW9662-treated colitis mice, the protective role was significantly weakened. Importantly, the administration of GW9662 significantly aggravated UC compared with the ZO + DSS group. In addition, we preliminarily found that ZO had the effects of inhibiting DSS-induced oxidative stress, maintaining intestinal barrier, and inhibiting the content of LPS and the population of Escherichia coli. CONCLUSIONS: These results indicated that supplementation with ZO might be a new dietary strategy for the treatment of UC. © 2022 Society of Chemical Industry.

Effect of gigantol on the proliferation of hepatocellular carcinoma cells tested by a network-based pharmacological approach and experiments.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common clinical malignant disease and the second leading cause of cancer-related death worldwide. Dendrobium is a commonly applied nourishing drug in traditional Chinese medicine. Gigantol is a phenolic compound extracted from Dendrobium. The compound has attracted attention for its anticancer effects. However, the mechanism of gigantol in HCC has not been extensively explored. METHODS: Potential targets of gigantol were predicted by SwissTargetPrediction. HCC-related genes were obtained from the GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), Therapeutic Target Database (TTD) and DrugBank databases. The "gigantol-target-disease" network was constructed using Cytoscape software. Protein interaction network analysis was performed using STRING software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were executed utilizing the R package to explore the possible regulatory mechanisms of gigantol in HCC. To authenticate the role of gigantol in HCC, Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, wound healing assay, Matrigel invasion assay and Western blot were performed. RESULTS: Three core genes were screened from 32 closely linked genes. Pathway analysis yielded many signaling pathways associated with cancer. The CCK-8 assay and EdU assay indicated that gigantol suppressed the growth of HCC cells. The wound healing assay and Matrigel invasion assay showed the inhibition of migration and metastasis of HCC cells by gigantol. We verified from molecular docking and protein level that gigantol can exert regulatory effects through three targets, ESR1, XIAP and HSP90AA1. Furthermore, Western blot results tentatively revealed that gigantol may inhibit HCC progression through the HSP90/Akt/CDK1 pathway. CONCLUSIONS: Our results confirms anti-HCC proliferation activity of gigantol through PI3K pathway described in existing literature by different experimental approaches. Furthermore, it has discovered other proteins regulated by the drug that was not previously reported in the literature.These findings provide potential molecular and cellular evidence that gigantol may be a promising antitumor agent.

Construction of an Artificial Biosynthetic Pathway for Zingerone Production in Escherichia coli Using Benzalacetone Synthase from Piper methysticum.

Zingerone (vanillylacetone; 4-hydroxy-3-methoxyphenylethyl methyl ketone) is a key component responsible for the pungency of ginger (Zingiber officinale). In this study, it was confirmed that a type III polyketide synthase (PKS) gene (pmpks) from Piper methysticum exhibits feruloyl-CoA-preferred benzalacetone synthase (BAS) activity. Based on these results, we constructed an artificial biosynthetic pathway for zingerone production from supplemented ferulic acid with 4-coumarate CoA ligase (4CL), PmPKS, and benzalacetone reductase (BAR). Furthermore, a de novo pathway for the production of zingerone was assembled using six heterologous genes, encoding tyrosine ammonia-lyase (optal), cinnamate-4-hydroxlase (sam5), caffeic acid O-methyltransferase (com), 4CL (4cl2nt), BAS (pmpks), and BAR (rzs1), in Escherichia coli. Using the engineered l-tyrosine-overproducing E. coli ΔCOS4 strain as a host, a maximum yield of 24.03 ± 2.53 mg/L zingerone was achieved by complete de novo synthesis.

Ginger, a Possible Candidate for the Treatment of Dementias?

As the human life expectancy increases, age-linked diseases have become more and more frequent. The worldwide increment of dementia cases demands medical solutions, but the current available drugs do not meet all the expectations. Recently the attention of the scientific community was attracted by natural compounds, used in ancient medicine, known for their beneficial effects and high tolerability. This review is focused on Ginger (Zingiber officinale) and explore its properties against Alzheimer's Disease and Vascular Dementia, two of the most common and devastating forms of dementia. This work resumes the beneficial effects of Ginger compounds, tested in computational in vitro and in vivo models of Alzheimer's Disease and Vascular Dementia, along with some human tests. All these evidences suggest a potential role of the compounds of ginger not only in the treatment of the disease, but also in its prevention.

Ginger: A complementary approach for management of cardiovascular diseases.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Inflammation and oxidative stress play critical roles in progression of various types of CVD. Broad pharmacological properties of ginger (the rhizome of Zingiber officinale) and its bioactive components have been reported, suggesting that they can be a therapeutic choice for clinical use. Consistent with its rich phenolic content, the anti-inflammatory and antioxidant properties of ginger have been confirmed in many studies. Ginger modifies many cellular processes and in particular was shown to have potent inhibitory effects against nuclear factor kappa B (NF-κB); signal transducer and activator of transcription; NOD-, LRR-, and pyrin domain-containing proteins; toll-like receptors; mitogen-activated protein kinase; and mammalian target of rapamycin signaling pathways. Ginger also blocks pro-inflammatory cytokines and the activation of the immune system. Ginger suppresses the activity of oxidative molecules such as reactive oxygen species, inducible nitric oxide synthase, superoxide dismutase, glutathione, heme oxygenase, and GSH-Px. In this report, we summarize the biochemical pathologies underpinning a variety of CVDs and the effects of ginger and its bioactive components, including 6-shogaol, 6-gingerol, and 10-dehydrogingerdione. The properties of ginger and its phenolic components, mechanism of action, biological functions, side effects, and methods for enhanced cell delivery are also discussed. Together with preclinical and clinical studies, the positive biological effects of ginger and its bioactive components in CVD support the undertaking of further in vivo and especially clinical studies.

Development of edible Thai rice film fortified with ginger extract using microwave-assisted extraction for oral antimicrobial properties.

This study aimed to investigate microwave-assisted extraction (MAE) of dried ginger and to develop a rice-based edible film incorporating ginger extract. The optimal MAE conditions of 400 W microwave power and an extraction time of 1 min were determined using a 32 full factorial design. The optimized extract showed total phenolic compounds (TPC, 198.2 ± 0.7 mg gallic acid equivalent/g), antioxidant activity measured by DPPH (91.4 ± 0.6% inhibition), ABTS (106.4 ± 3.1 mg Trolox/g), and FRAP (304.6 ± 5.5 mg Trolox/g), and bioactive compounds including 6-gingerol (71.5 ± 3.6 mg/g), 6-shogaol (12.5 ± 1.0 mg/g), paradol (23.1 ± 1.1 mg/g), and zingerone (5.0 ± 0.3 mg/g). Crude extract of dried ginger showed antimicrobial activity against Streptococcus mutans DMST 18777, with a minimum inhibitory concentration and minimum bactericidal concentration of 0.5 and 31.2 mg/mL, respectively. The rice-based edible film incorporating 3.2% (w/v) ginger extract tested against S. mutans DMST 18777 had a mean zone of inhibition of 12.7 ± 0.1 mm. Four main phenolic compounds, 6-gingerol, 6-shogaol, paradol, and zingerone, and six volatile compounds, α-curcumene, α-zingiberene, γ-muurolene, α-farnesene, ß-bisabolene, and ß-sesquiphellandrene, were found in rice film fortified with crude ginger extract.

6-Paradol Acts as a Potential Anti-obesity Vanilloid from Grains of Paradise.

SCOPE: Grains of Paradise (GOP), the seeds of Aframomum melegueta, has anti-obesity effects. However, the mechanisms underlying the effects remain unclear. METHODS AND RESULTS: This study sets up to study the anti-obesity impact and homeostatic effects of 6-paradol, a major vanilloid found in GOP, and investigates the physiological outputs and the lipometabolism-related gene in fat and liver in high-fat-induced obese mice with a comparison with structurally similar vanilloids (6-gingerol and 6-shogaol). The vanilloids are synthesized in adequate quantities for performing animal experiments and orally administered to 6-week-old male mice over 2 weeks. This study found that 6-paradol decreased body weight gain and visceral and subcutaneous fats in 2 weeks, whereas 6-gingerol and 6-shogaol have no effect. Additionally, 6-paradol suppresses the hepatic cholesterol and triglyceride and significantly decreases the gene expression related to fatty acid synthesis, lipid transportation, and adipocyte differentiation in both liver and adipose tissue. Moreover, phosphorylation of AMP-activated protein kinase (AMPK) that greatly contributes to lipometabolism is promoted by 6-gingerol but not 6-paradol. CONCLUSION: These results suggest that 6-paradol regulates several obesity-related genes in an AMPK-independent manner. Therefore, it could be the principal active vanilloid in GOP giving it anti-obesity properties with a different mechanism.

Zingerone (4-(four-hydroxy-3-methylphenyl) butane-two-1) modulates adjuvant-induced rheumatoid arthritis by regulating inflammatory cytokines and antioxidants.

OBJECTIVE: Ginger (Zingiber officinale Roscoe) is considered to be one of the most commonly consumed dietary condiments of the world. The present study was designed to explicate the protective role of zingerone; an active ingredient of ginger in complete Freund's adjuvant (FCA)-immunized arthritic rats. METHODS: 24 Wistar rats were divided into 4 groups with 6 rats each. Group I as control followed by group II, III and IV were treated with single intradermal injection of FCA (0.1 ml = 100 µg) to induce rheumatoid arthritis. Group III and IV were also administered with zingerone orally at 25 mg/kg b.w for 3 weeks at two different time points. RESULTS: Adjuvant-treated rats exhibited a significant increase in lipid peroxidation and a reduction in the enzymatic antioxidants such as SOD, catalase and GPx, in the liver and joint tissues. Moreover, FCA inoculation resulted in the increase in levels of NF-κB, TGF-ß, TNF-α, IL-1ß, IL-6 and Hs-CRP and a decrease in IL-10 levels. Zingerone significantly reduced the levels of NF-κB, TGF-ß, TNF-α, IL-1ß, IL-6 and Hs-CRP and markedly increased IL-10 levels. Levels of antioxidant enzymes were also restored by zingerone treatment. DISCUSSION: Oral administration of zingerone ameliorated inflammatory outburst and decreased oxidative stress, suggesting its role in the prevention of rheumatoid arthritis. Further mechanistic insights are necessary to study the exact mechanism involved.

The protective role of Zingerone in a murine asthma model via activation of the AMPK/Nrf2/HO-1 pathway.

Asthma is one of the most common illnesses associated with chronic airway inflammation; however, there are currently no effective therapies apart from glucocorticoids. Zingerone (ZIN), an active compound isolated from ginger, has been reported to have a broad spectrum of pharmacological properties. In this study, Zingerone was administrated to H2O2-stimulated mouse airway epithelial cell line MLE12 cells and asthmatic mice. The concentration of cytokines was evaluated using enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE), Periodic Acid-Schiff (PAS) and Masson staining were used for histological analyses. Protein levels in cells or lung tissues were determined using western blot, immunohistochemistry staining. The results showed that treatment with Zingerone dramatically inhibited oxidative stress and the inflammatory response in MLE12 cells stimulated with H2O2 and asthmatic mice. Furthermore, Zingerone treatment could decrease the expression of phosphorylated (p)-IκBα and p65 (nuclear) and increase the expression of phosphorylation of AMP-activated protein kinase (p-AMPK), nuclear factor erythroid-2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1) to alleviate oxidative damage and inflammation both in vivo and in vitro. In addition, Zingerone treatment reduced the exudation and infiltration of inflammatory cells and suppressed goblet cell hyperplasia in a murine asthma model. Treatment with Zingerone also decreased the level of interleukin (IL)-4, IL-5, IL-13, and increased the level of interferon gamma (IFN-γ) in the BALF and attenuated airway hyperresponsiveness (AHR). However, inhibition of AMPK or Nrf2 suppressed the cellular protective, antioxidative, and anti-inflammatory properties of Zingerone. Taken together, these results demonstrate that Zingerone possesses the potential to relieve asthma via upregulating the AMPK/Nrf2/HO-1 signaling pathway.

Zingerone improves the immune responses in an animal model of breast cancer.

OBJECTIVES: The potent anti-tumorigenic effects were attributed to ginger and there are some reports regarding the anti-cancer and immunomodulatory properties ginger-derived components. This study aimed to investigate the effects of zingerone on some immune-related parameters in an animal model of breast cancer. METHODS: The breast cancer was established in female BALB/c mice using a carcinogenic 4T1 cell line. At day 10 after cancer induction, tumor-bearing mice were divided into five groups and treated intraperitoneal (daily from days 11-30) with saline or zingerone (at doses 10, 20, 50 and 100 mg/kg/day). The mice were sacrificed on day 31 and the number of splenic Th1- and Treg cells, the expression of IFN-γ and TGF-ß in the blood mononuclear cells, the antibody production against sheep red blood cell (SRBC) were determined using flow cytometry, real time-PCR and a standard hemagglutination assay, respectively. RESULTS: Zingerone at doses 50 and 100 mg/kg enhanced the number of splenic Th1 cells (p<0.03 and 0.007, respectively); at doses 10, 20, 50 and 100 mg/kg reduced the number of splenic Treg cells (p<0.02, 0.01, and 0.01, respectively), at doses 50 and 100 mg/kg enhanced the expression of IFN-γ (p<0.03), at doses 50 and 100 mg/kg reduced the expression of TGF-ß, at doses 50 mg/kg reduced the titer of anti-SRBC antibody (p<0.05). CONCLUSIONS: Zingerone improve the T cell-mediated and antibody responses in a mouse model of breast cancer. The immunotherapeutic potentials of zingerone in cancers need more considerations.

Zingerone Administered Neonatally Prevents the Subsequent Development of High Dietary Fructose-Induced Fatty Liver in Sprague Dawley Rats.

Consumption of high-fructose diets early in life increases the risk of developing metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). Zingerone, an alkaloid isolated from Zingiber officinale, has been demonstrated to reverse obesity and fatty liver in adult male rats. We investigated the potential preventive effects of neonatally administered zingerone on the development of fructose-induced NAFLD in male and female rats. Four-day-old male (n = 35) and female (n = 44) rat pups were randomized and gavaged with: 10 mL/kg body weight (bwt) of distilled water (C), 10 mL/kg bwt of 20% fructose solution (Fr), 10 mL/kg bwt of 20% fructose solution +40 mg/kg bwt of zingerone (ZFr), and 40 mg/kg bwt of zingerone (Z) daily for 14 days. After weaning, all groups continued on unlimited standard rat feed; however, groups C and Z had plain drinking water, whereas groups Fr and ZFr had unlimited 20% fructose solution to drink for 10 weeks. Rats on the high-fructose diet (Fr) compared with the negative controls (C) had significantly increased hepatic lipid content (in %, males: P = .0002; females: P < .0001, analysis of variance [ANOVA]) and hepatic steatosis score (in %, males: P = .0018; females: P < .0022, Kruskal-Wallis ANOVA). Zingerone prevented (P < .05) the fructose-induced increase in hepatic steatosis in both sexes. The plasma alanine aminotransferase activity, levels of uric acid, TBARS (thiobarbituric acid reactive substances), IL-6 (interleukin-6), and TNF-α (tumor necrosis factor alpha) were not different (P > .05, ANOVA) across the different treatment groups in both sexes. No difference (P > .05, ANOVA) was observed between the two sexes for treatment, sex and interaction effects with regard to hepatic lipid content, and measured blood parameters. The use of zingerone neonatally should be further investigated as a strategic prophylactic intervention for the prevention of long-term high-fructose diet-induced NAFLD.

Neonatal zingerone protects against the development of high-fructose diet-induced metabolic syndrome in adult Sprague-Dawley rats.

During the early postnatal period, dietary manipulations can alter the developmental trajectory of the growing offspring, causing beneficial or adverse health outcomes later in adult life. We investigated the potential preventive effects of neonatal zingerone intake on the development of fructose-induced metabolic derangements in rats.Four-day old male and female Sprague-Dawley rat pups (n = 79) were randomly grouped and administered: 10 ml/kg body weight (bwt) of distilled water (W), 10 ml/kg bwt 20% fructose solution (FS), 10 ml/kg bwt fructose solution + 40 mg/kg bwt of zingerone in distilled water (ZF) or 40 mg/kg bwt of zingerone in distilled water (ZW) pre-weaning. After weaning, W and ZW continued on unlimited tap water, while FS and ZF continued on unlimited fructose solution for 10 weeks. Body mass and food and fluid intake were evaluated, plasma was collected for metabolic assays and visceral fat was quantified.Food intake was decreased, fructose and overall caloric intake were increased due to fructose feeding in both sexes (P < 0.05). When compared with the controls, the high-fructose diet significantly raised the terminal body masses of females (P < 0.0001), concentrations of triglycerides, total cholesterol, LDL-c, TG:HDL-c ratio and visceral fat mass relative to bwt in both sexes (P < 0.05). Zingerone prevented (P < 0.05) the fructose-induced increase in body mass (females) and hypercholesterolemia (both sexes). Levels of HDL-c, glycaemic parameters and adiponectin were not affected by the interventions (P > 0.05). Sex-related differences were observed in food, fluid and caloric intake, terminal mass, cholesterol subtypes and visceral fat percentage (P < 0.05).Zingerone could be used strategically in the neonatal phase as a prophylatic management of high-fructose diet-induced metabolic syndrome.

6-Paradol and its glucoside improve memory disorder in mice.

In this study, the effects of 6-paradol (6P) and 6-paradol-ß-glucoside (6PG) on neuritogenesis were investigated using PC12 cells. Treatment with 200 µM 6P or 6PG and nerve growth factor (NGF) (5 ng mL-1) increased the number of elongated dendritic cells 8.7 and 5.4 times, respectively, compared to that with NGF (5 ng mL-1) treatment alone. 6P and 6PG did not stimulate the phosphorylation of extracellular regulated protein kinases (ERK)1/2 and cAMP response element-binding protein (CREB) in the tropomyosin receptor kinase A (TrkA) pathway as their activities were suppressed by the pathway inhibitor, k252a. 6P enhanced Ca2+ influx into the cells, whereas 6PG had no effect on Ca2+ influx, although it stimulated PC12 cell differentiation. High-performance liquid chromatography (HPLC) analysis of 6PG in PC12 culture medium suggested that 6PG was deglycosylated to generate 6P, which exhibited the effect. Furthermore, the bioactivities of 6P and 6PG were investigated in mice, and the results revealed that they ameliorated short-term memory loss in animals during behavioral testing.

Immune modulatory effect of a novel 4,5-dihydroxy-3,3´,4´-trimethoxybibenzyl from Dendrobium lindleyi.

Dendrobium bibenzyls and phenanthrenes such as chrysotoxine, cypripedin, gigantol and moscatilin have been reported to show promising inhibitory effects on lung cancer growth and metastasis in ex vivo human cell line models, suggesting their potential for clinical application in patients with lung cancer. However, it remains to be determined whether these therapeutic effects can be also seen in primary human cells and/or in vivo. In this study, we comparatively investigated the immune modulatory effects of bibenzyls and phenanthrenes, including a novel Dendrobium bibenzyl derivative, in primary human monocytes. All compounds were isolated and purified from a Thai orchid Dendrobium lindleyi Steud, a new source of therapeutic compounds with promising potential of tissue culture production. We detected increased frequencies of TNF- and IL-6-expressing monocytes after treatment with gigantol and cypripedin, whereas chrysotoxine and moscatilin did not alter the expression of these cytokines in monocytes. Interestingly, the new 4,5-dihydroxy-3,3',4'-trimethoxybibenzyl derivative showed dose-dependent immune modulatory effects in lipopolysaccharide (LPS)-treated CD14lo and CD14hi monocytes. Together, our findings show immune modulatory effects of the new bibenzyl derivative from Dendrobium lindleyi on different monocyte sub-populations. However, therapeutic consequences of these different monocyte populations on human diseases including cancer remain to be investigated.

In vivo Screening of Natural Products Against Angiogenesis and Mechanisms of Anti-Angiogenic Activity of Deoxysappanone B 7,4'-Dimethyl Ether.

INTRODUCTION: The aim of this study was to screen the leading compounds of natural origin with anti-angiogenic potential and to investigate their anti-angiogenic mechanism preliminarily. MATERIALS AND METHODS: An initial screening of 240 compounds from the Natural Products Collection of MicroSource was performed using the transgenic zebrafish strain Tg [fli1a: enhanced green fluorescent protein (EGFP)]y1 . The zebrafish embryos at 24 h post-fertilization were exposed to the natural compounds for an additional 24 h; then, morphological changes in the intersegmental vessels (ISVs) were observed and quantified under a fluorescence microscope. The expression profiles of angiogenesis-related genes in the zebrafish embryos were detected using quantitative real-time PCR. RESULTS: Five compounds were identified with potential anti-angiogenic activity on the zebrafish embryogenesis. Among them, deoxysappanone B 7.4'-dimethyl ether (Deox B 7,4) showed anti-angiogenic activity on the formation of ISVs in a dose-dependent manner. The inhibition of ISV formation reached up to 99.64% at 5 µM Deox B 7,4. The expression of delta-like ligand 4 (dll4), hes-related family basic helix-loop-helix transcription factor with YRPW motif 2, ephrin B2, fibroblast growth factor receptor (fgfr) 3, cyclooxygenase-2, protein tyrosine phosphatase, receptor type B (ptp-rb), phosphoinositide-3-kinase regulatory subunit 2, slit guidance ligand (slit) 2, slit3, roundabout guidance receptor (robo) 1, robo2, and robo4 were down-regulated, while vascular endothelial growth factor receptor-2, fgfr 1, and matrix metallopeptidase 9 were up-regulated in the zebrafish embryos treated with Deox B 7,4. CONCLUSION: Deox B 7,4 has a therapeutic potential for the treatment of angiogenesis-dependent diseases and may exert anti-angiogenic activities by suppressing the slit2/robo1/2, slit3/robo4, cox2/ptp-rb/pik3r2, and dll4/hey2/efnb2a signaling pathways as well as activation of vegfr-2/fgfr1/mmp9.

Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver.

In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl4-induced acute liver injury, pre-administration of gigantol (10, 20, 40 mg· kg-1· d-1, po, for 7 days) dose-dependently decreased serum transaminase levels and improved pathological changes in liver tissues. The elevated lipid peroxidation and inflammatory responses in the livers were also significantly alleviated by gigantol. The pharmacokinetic studies showed that gigantol was highly concentrated in the mouse livers, which consisted with its efficacy in preventing liver injury. Using a label-free quantitative proteomic analysis we revealed that gigantol mainly regulated the immune system process in liver tissues of CCl4-treated mice, and the complement and coagulation cascades was the predominant pathway; gigantol markedly inhibited the expression of complement component C9, which was a key component for the formation of terminal complement complex (TCC) C5b-9. These results were validated by immunohistochemistry (IHC) or real time-PCR. Confocal microscopy analysis showed that gigantol significantly inhibited the vascular deposition of TCC in the liver. In conclusion, we demonstrate for the first time that oral administration of gigantol potently relieves liver oxidative stress and inflammation, possibly via a novel mechanism of inhibiting the C5b-9 formation in the liver.